U.S. patent number 5,208,225 [Application Number 07/781,568] was granted by the patent office on 1993-05-04 for compositions containing fixed combinations.
This patent grant is currently assigned to Warner-Lambert Company. Invention is credited to Roger M. Boissonneault, Henry A. Miller, Jr..
United States Patent |
5,208,225 |
Boissonneault , et
al. |
May 4, 1993 |
Compositions containing fixed combinations
Abstract
Continuous administration of compositions containing a fixed
quantity of synthetic estrogen in combination with a synthetic
progestogenic agent are useful to relieve menopausal symptoms, to
prevent osteoporosis and for other hormone-replacement treatments.
Also described is an improved manufacturing process for such
compositions especially for low tablet dosage forms.
Inventors: |
Boissonneault; Roger M. (Long
Valley, NJ), Miller, Jr.; Henry A. (Lake Hopatcong, NJ) |
Assignee: |
Warner-Lambert Company (Morris
Plains, NJ)
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Family
ID: |
27119878 |
Appl.
No.: |
07/781,568 |
Filed: |
October 22, 1991 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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647189 |
Jan 24, 1991 |
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366796 |
Jun 15, 1989 |
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168106 |
Mar 14, 1988 |
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73367 |
Jul 6, 1987 |
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834263 |
Feb 26, 1986 |
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Current U.S.
Class: |
514/178; 514/182;
514/843; 514/899 |
Current CPC
Class: |
A61K
31/57 (20130101); A61K 31/57 (20130101); A61K
2300/00 (20130101); Y10S 514/843 (20130101); Y10S
514/899 (20130101) |
Current International
Class: |
A61K
31/57 (20060101); A61K 031/56 () |
Field of
Search: |
;514/169,170,171,178,182,843,899 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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8431405 |
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Jul 1985 |
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AU |
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136011 |
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Mar 1985 |
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EP |
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Other References
Abstract from "Abstracts of Current, Clinical and Basic
Investigation" 35th Annual Clinical Meeting, Apr. 27-30, Las Vegas,
Nev. .
British Journal of Obstetrics and Gynecology, vol. 94, pp. 130-135,
published Feb. 1987. .
The Lancet, Oct. 12, 1985, by C. Christiansen, et al. p. 800,
column 2. .
Acta Obstet Gynecol Scand 63:673-677, (1984) by Mattsson, et al.
(See p. 673, column 2 last paragraph). .
Elsevier Biomedical Press (1982), article by L. A. Mattsson, et
al., p. 95 (See p. 96, section entitled "Material and Methods".
.
The Medical Journal of Australia, 1974, pp. 688-690. .
Acta Object Gynecol Scand Suppl 106:17-22, 1982. .
Obstetrics & Gynecology, 1983, pp. 682-686. .
Aust. N.Z.J. Obstet Gynaec., 1983, pp. 43-47. .
Collection of chapters from "Hormone Therapy of the Menopause and
Aging". .
The Merck Index; 10th Ed. (1983); pp. 542, 960..
|
Primary Examiner: Waddell; Frederick E.
Assistant Examiner: Criares; T. J.
Attorney, Agent or Firm: Daignault; Ronald A.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Ser. No. 647,189
of Jan. 24, 1991, now abandoned which is a continuation of U.S.
Ser. No. 366,796 of Jun. 15, 1989, now abandoned, which is a
continuation-in-part of U.S. Ser. No. 168,106 of Mar. 14, 1988, now
abandoned, which is a continuation in-part of U.S. Ser. No. 073,367
of Jul. 6, 1987, now abandoned, which is a continuation of U.S.
Ser. No. 834,263 of Feb. 26, 1986, now abandoned.
Claims
I claim:
1. A method for treating menopausal symptoms associated with
hormone deficiency in a postmenopausal female host comprising
continuous, daily administration to said host of a fixed
combination in the form of a pharmaceutical composition for oral
administration comprising:
(a) about 1-20 mcg ethinyl estradiol, and
(b) about 0.1-1.0 mg norethindrone acetate, wherein the ratio of
norethindrone acetate to ethinyl estradiol is about 50:1 to about
200:1.
2. The method of claim 1, wherein the composition comprises:
(a) 1-10 mcg ethinyl estradiol, and
(b) 0.1-1 mg norethindrone acetate, wherein the ratio of
norethindrone acetate to ethinyl estradiol is about 100:1 to about
200:1.
3. The method of claim 2, wherein the composition comprises 1 mcg
ethinyl estradiol and 0.2 mg norethindrone acetate.
4. The method of claim 2, wherein the composition comprises 2.5 mcg
ethinyl estradiol and 0.5 mg norethindrone acetate.
5. The method of claim 2, wherein the composition comprises 5 mcg
ethinyl estradiol and 1 mg norethindrone acetate.
6. The method of claim 2, wherein the composition comprises 10 mcg
ethinyl estradiol and 1 mg norethindrone acetate.
Description
BACKGROUND
The treatment of menopausal symptoms such as flashing, osteoporosis
and other symptoms associated with hormone deficiency is old.
Typically, the known formulations for such treatment have contained
natural estrogen or other estrogenic component(s) as the only
hormonal ingredient. Known formulations were designed to treat
symptoms rather than to replace the physiologic deficiency that
results from dysfunctional ovaries. Also known formulations were
marketed without adequate dose ranging and dosed in a cyclic
fashion. The administration of estrogen in a cyclic fashion was an
attempt to rest the endometrium from the continuous stimulation of
estrogen. This practice is questionable in that the half-life of
equine estrogens can be long (lipid soluble) and the patient never
falls out of therapeutic range. As a result, despite cyclic
administration, the replacement of estrogen with these types of
formulations containing estrogen only has led to evidence of
hyperstimulation of the endometrium and, in some cases, subsequent
adenocarcinoma.
To minimize the potential for hyperstimulation, 5-14 days of
progestional therapy has been included on a monthly basis to slough
the endometrium. As a result, the patient experiences a monthly
withdrawal bleed similar to the premenopausal state. Market
research with physicians indicates that the nuisance of this cyclic
bleeding is the single most important reason postmenopausal females
refuse or discontinue therapy. Although progestins protect against
hyperstimulation, they have been associated with a negative effect
on blood lipids. As opposed to estrogen's positive effect on
lipids, e.g., increase HDL/lower LDL, progestin's negative effect
on lipids may compromise the cardioprotective state of the
premenopausal female.
THE INVENTION
Applicant has discovered that a fixed combination of estrogenic and
progestogenic agents gives relief from menopausal symptoms with
minimal side effects. In one preferred embodiment, a composition
containing a fixed dosage of ethinyl estradiol, --i.e., 0.001-0.05
mg-- along with a fixed dosage of norethindrone acetate --i.e.,
0.1-1.0 mg-- yields, when administered in a continuous sequence,
acceptable hormone levels in patients.
Thus, the invention is concerned with compositions and methods in
which a formulation containing a fixed estrogen/progestin ratio is
administered to female individuals with resultant relief from hot
flashes, osteoporosis and other conditions associated with hormone
deficiency.
The invention is also concerned with a new process for preparing
fixed combinations of norethindrone acetate and ethinyl estradiol,
especially useful for low tablet dosage forms where the ratio of
norethindrone acetate may be from about 1:100 to about 1:1000 and
ethinyl estradiol from about 1:2000 to about 1:100,000, the final
tablet weight. The process employs a two-component drug dilution
introduced onto tableting excipients.
ADVANTAGES
The compositions and processes of the invention have several
advantages over those already known in the art. Principal among
their advantages are:
1. The compositions contain fixed, i.e., constant or unitary,
quantities of both the estrogenic and progestogenic agents. This
simplifies manufacturing, storage, and packaging.
2. The use of a continuously dosed product minimizes patient
compliance problems associated with an alternating sequence of dual
therapies.
3. The administration of a single combination product containing
fixed quantities of hormonal agents is psychologically beneficial.
Also it has been demonstrated that low doses of this combination of
hormones results in an atrophic state that obviates the troublesome
side effect of monthly withdrawal bleeding.
4. Through the use of dose ranging the invention is designed to
replace that which is physiologically lost rather than treat
symptoms with supraphysiologic doses of estrogen and progestin. The
result is a therapy that is associated with a relatively low
incidence of side effects.
5. The invention has demonstrated efficacy similar to existing
therapy (20 mcg, ethinyl estradiol), however, at one-fourth the
total dose of estrogen. As a result the margin of safety
(thromboembolism) has been expanded as measured by effects on
clotting factors and angiotensin levels.
6. Ultra low doses of estrogen/progestin dosed in a schedule
consistent with the postmenopausal state of endogenous hormone
production offers protection against hot flashes, osteoporosis,
endometrial hyperplasia, cyclic bleeding, and potentially
replicates the cardioprotective state of the premenopausal
female.
7. The use of the new and improved process for preparing low tablet
dosage forms involving the combination of two drugs in one solution
eliminates any error that may occur with distribution of one drug
more than the other.
8. The new process also provides for processing to be carried out
in one piece of equipment, e.g., a P-K solids processor, from
blending to addition of lubricant thereby eliminating the need for
transfer and drying.
9. Other aspects and advantages of the invention will be made
apparent by the following description and claims.
DESCRIPTION OF THE INVENTION
The compositions and methods of the invention are based upon the
use of a novel combination of synthetic estrogenic and
progestogenic ingredients.
The compositions generally contain about 0.001 to 0.05 parts by
weight, preferably about 0.001 to about 0.02 parts, or more
preferably about 0.001 to 0.01 parts of the estrogenic ingredient
and about 0.1 to about 1.0 parts by weight of the progestogenic
ingredient.
Generally, the ratios by weight of progestogenic to estrogenic
components in the inventive compositions will be from about 20:1 to
about 200:1, preferably about 50:1 to about 200:1, and more
preferably about 100:1 to about 200:1.
While milligrams are the preferred units of measurement, any scale
can be used so long as the ratio of the active hormonal ingredients
remains fixed and is appropriate to the weight ratios set out
above. For example, in especially low tablet dosage forms,
micrograms are often used as the units of measurement.
The estrogenic ingredient of the inventive compositions can be any
suitable synthetic estrogen or functional equivalent thereof. While
ethinyl estradiol is the preferred estrogenic substance, other
useful substances include conjugated estrogens, estrone sulfate,
beta estradiol, quinestrol, and the like. Mixtures are
operable.
The progestogenic ingredient is generally a synthetic progestogen;
however, natural progestins may be used. Useful progestogenic
substances include medroxyprogesterone, medroxyprogesterone
acetate, norgestrel, desogestrel, and the like. Norethindrone
acetate is preferred. Mixtures are operable.
While it is preferred that the synthetic estrogen and progestin be
the only pharmaceutically active ingredients in the compositions,
the use of other drugs and/or otherwise beneficial substances in
the instant compositions is contemplated.
The use of conventional pharmaceutical carriers is contemplated.
Other excipients such as perfumes, colorants, stabilizers, fillers,
and the like can be used as well.
The compositions of the invention can be administrated via a
variety of routes. Any method or combination of method by which a
continuous dosage form can be administered is operable. Oral dosage
forms are preferred.
When oral dosage forms are employed, it is generally preferred that
they be solid or semisolid. However, liquid compositions are
contemplated.
One aspect of the invention involves the packaging of the
compositions of the invention, in a solid dosage form, in a pill
case or compact for continuous administration. Thus, a package
similar to that sometimes used for dispensing contraceptive pills,
tablets, and the like can be employed. Thus, the individual who is
to ingest the subject composition merely takes the pills, tablets,
and/or capsule in a daily regimen.
In general, any dosage form and packaging concept can be used in
combination so long as the composition is administered at least
once daily in a continuous sequence.
More preferred dosage forms for the above regimen are those
compositions containing a fixed dosage of ethinyl estradiol, 1-20
micrograms (mcg), with a fixed dosage of norethindrone acetate,
0.1-1.0 milligrams (mg), wherein the ratio of norethindrone acetate
to ethinyl estradiol is from about 50:1 to about 200:1. Most
preferred contain a fixed dosage of 1-10 mcg ethinyl estradiol and
0.1-1.0 mg norethindrone acetate, wherein the ratio of
norethindrone acetate to ethinyl estradiol is from about 100:1 to
about 200:1.
Particularly valuable compositions contain as active
ingredients:
1 mcg ethinyl estradiol and 0.2 mg norethindrone acetate;
2.5 mcg ethinyl estradiol and 0.5 mg norethindrone acetate;
5 mcg ethinyl estradiol and 1 mg norethindrone acetate, and
10 mcg ethinyl estradiol and 1 mg norethindrone acetate.
The compositions of the invention are useful for treating
osteoporosis, hot flashes, withdrawal bleeding, and other disorders
and symptoms generally associated with hormone deficiency, many of
which are experienced during menopause.
Thus, for example, in a blinded, prospective, dose-response pilot
study of continuous estrogen-progestin replacement therapy, 77
thin, nonsmoking, white women, who were 12 to 60 months
postmenopausal and had normal medical histories, were randomly
assigned to receive one of five dose combinations of daily ethinyl
estradiol and norethindrone acetate (20 mcg and 1.0 mg, 10 mcg and
1.0 mg, 10 mcg and 0.5 mg, 5 mcg and 1.0 mg, and 5 mcg and 0.5 mg)
or conjugated estrogens 0.625 mg on Days 1 to 25 and
medroxyprogesterone acetate 10 mg on Days 16 to 25. An additional
10 women meeting the same criteria served as a comparison group by
taking calcium only. During 12 months of therapy, continuous users
had significantly less vaginal bleeding and spotting than did
sequential users. As compared with baseline values, bone
metabolism, and computerized tomographic measurements of vertebral
trabecular bone density at Month 12 indicated reduced bone turnover
and increased density in hormone users. Endometrial biopsy
specimens were negative for hyperplasia and neoplasia. The
continuous ethinyl estradiol-norethindrone acetate tablet, even at
the lowest doses studied, provided the same salutary effects on
bone, endometrium and postmenopausal symptoms as sequential therapy
while minimizing annoying vaginal bleeding and spotting.
MATERIAL AND METHODS
Advertisements in Cleveland newspapers requested postmenopausal
women to volunteer in a study of estrogen replacement.
Approximately 150 respondents were screened by telephone interview
according to these inclusion criteria: (1) 12 to 60 months had
passed since natural menopause (time since last menstrual
bleeding); (2) they were white or Oriental; (3) they were within
10% of ideal body weight for height and frame (Metropolitan
Insurance Company standards); (4) they had not received hormonal
therapy for the last 3 months; (5) they did not smoke; (6) their
medical histories were negative for carcinoma, hypertension,
diabetes, mellitus, disease of the liver, gallbladder disease,
heart or vascular system diseases, alcoholism, and corticosteroid
therapy. These criteria were designed to select a sample of women
who were at risk for osteoporosis and were homogenous in factors
related to metabolism of estrogen. Ninety-five women were eligible
to participate in the study. These women were invited to undergo a
thorough baseline evaluation, which included a history, physical
examination, electrocardiogram, mammogram, endometrial biopsy, and
routine blood chemistry tests. Eight other women were excluded; all
of the remaining 87 women who met the inclusion criteria gave
informed consent to participate in the study, as approved by the
Investigational Review Board of the University Hospitals of
Cleveland.
Rather than exclude the 10 women who did not wish to take hormones,
we decided to administer calcium carbonate, 1000 mg daily (os-Cal
500 b.i.d., Marion Laboratories, Kansas City, Mo.), and undertake
follow-up of these women. They formed a self-selected
"calcium-only" group (Group A) and had the same demographic
characteristics and medical surveillance as the other participants.
Along with the 1000 mg daily dose of calcium carbonate, the
remaining 77 women were randomly allocated to receive either
sequential estrogen-progestin therapy or one of five dose
combinations of continuous therapy (Table I). The latter six groups
(B through G) constituted the principal focus of the study.
TABLE I ______________________________________ Treatment Schedule
Group n Treatment* ______________________________________ A:
Calcium only 10 No hormone replacement B: Sequential 12
Conventional combination therapy: Conjugated equine estrogens 0.625
mg Days 1-25 and medroxyprogesterone acetate 10 mg Days 16-25 C:
20/1 Continuous 12 Daily ethinyl estradiol 20 mcg and norethindrone
acetate 1.0 mg D: 10:1 Continuous 14 Daily ethinyl estradiol 10 mcg
and norethindrone acetate 1.0 mg E: 10/0.5 Continuous 13 Daily
ethinyl estradio1 10 mcg and norethindrone acetate 0.5 mg F: 5/1
Continuous 14 Daily ethinyl estradiol 5 mcg and norethindrone
acetate 1.0 mg G: 5/0.5 Continuous 12 Daily ethinyl estradiol 5 mcg
and norethindrone acetate 0.5 mg
______________________________________ *All patients received 1000
mg calcium carbonate daily Participants who refused hormone
therapy
In the women receiving sequential therapy, the study could not be
blinded because they were required to take two pills daily with a
cyclic schedule (Group B). With continuous therapy (Groups C
through G), women consumed a single tablet of ethinyl estradiol and
norethindrone acetate. Although aware of membership in the
continuous treatment group, participants and investigators were
blinded to dose. Throughout the study, data excerpters and those
performing laboratory and radiologic measurements remained
completely blinded to group membership.
Data collection included a history, physical examination,
electrocardiogram, mammography, and information on menopausal
symptoms, endometrial histologic features, bone activity, and lipid
metabolism. Baseline data were obtained (0 months of treatment),
and thereafter measurements were done according to the schedule
outlined in Table II.
TABLE II ______________________________________ Studies Done During
the 12-Month Observation Period Study Months of Therapy
______________________________________ History, physical
examination, 0, 12 and mammography Symptom analysis By diary 1, 2
By interview 0, 2, 4, 6, 8, 10, 12 Bone activity Bone GIa, alkaline
0, 1, 6, 12 phosphatase, calcium, phosphorus Urine sampling 0, 1,
6, 12 Quantitative computerized 0, 12 tomography of lumbar spine
Lipid metabolism Total cholesterol, 0, 2, 6, 12 triglycerides, and
lipid fractions ______________________________________
During the baseline interview, women reported duration of
menopause, frequency of hot flushes (number per day), and
incidences of vaginal bleeding and spotting. Participants were
instructed to record their symptoms daily in a diary. After the
first 2 months of treatment, data on menopausal symptoms were
assessed by interview only.
Endometrial biopsies were performed by the investigators at 0 and
12 months with the women under paracervical block anesthesia, by
Vabra suction curettage (Berkeley Medevices Inc., Berkeley,
Calif.). Women randomized to sequential therapy underwent biopsy
between Cycle Days 21 and 25. All tissue samples were fixed in
formalin, labeled for blinding purposes, and then interpreted by
attending pathologists of the University Hospitals of
Cleveland.
At baseline and after 12 months of treatment, participants
underwent quantitative computerized tomography of the trabecular
portion of L1-3 vertebral bodies. A siemens DR3 system (Siemens AG,
Iselin, N.J.) and the CIRS model 4 lumbar simulator (Computerized
Imaging Reference Systems, Norfolk) were used. This phantom uses a
solid resin reference plug rather than the liquid reference
material used in the Genant phantom, making it less susceptible to
variation over time. Hounsfield numbers were obtained and calcium
hydroxyapatite content was calculated with the CIRS data graphic
correlation. The scan technique used 96 kV and 150 mA. Values for
L1, L2, and L3 were averaged, yielding a coefficient of variation
of 1.5% to 2.0%.
Blood specimens for serum total cholesterol, low-density
lipoprotein (LDL), high-density lipoprotein (HDL), very-low-density
lipoprotein (VLDL), triglyciderides, total alkaline phosphatase,
phosphorus, and total calcium were collected by venipuncture the
morning after an overnight fast, into Vacutainer serum separator
tubes (Becton-Dickinson, Rutherford, N.J.). Plasma specimens for
bone Gla protein (osteocalcin) were collected in citrated
Vacutainer tubes. Plasma and serum were separated by centrifugation
after 30 minutes was allowed for clotting. The serum alkaline
phosphatase, phosphorus, and total calcium assays were performed
the morning of collection with the sequential Multiple Analyzer
with Computer (SMAC) system (Technicon Corporation, Tarrytown,
N.Y.). Total cholesterol was estimated by the SMAC
Liebemann-Burchard reaction and triglycerides by the SMAC lipase
method. HDL cholesterol was precipitated by magnesium and dextran,
then assayed in the CoBas Bio centrifugal analyzer (Roche
Diagnostics, Nutley, N.J.). LDL cholesterol was calculated by the
formula: LDL=Total cholesterol-HDL-Triglycerides/6.25.
Plasma for Gla protein analysis was frozen at -70.degree. C. and
stored until completion of the study, when it was measured by Dr.
C. Christiansen in Denmark, utilizing a radioimmunoassay with an
antibody raised in rabbits to calf bone Gla protein. Urine samples
were collected the morning after an overnight fast and after 48
hours of avoidance of gelatins and soups. Participants were
instructed to void 2 hours before the appointment, drink
approximately 24 ounces of tap water, then collect the urine
specimen at our office. Assays for urinary calcium and creatinine
were performed the morning of collection, while aliquots for
measurement of hydroxyproline were frozen at -30.degree. C and
stored until the end of the study. Urinary creatinine was assayed
by a colorimetric method that used the Jaffe reaction of a CoBas
Bio centrifugal analyzer. The urinary calcium level was determined
by the Hitachi 705 calcium method. Urinary hydroxyproline assays
were run at the completion of the study using a cation exchange
resin and a colorimetric method.
Where appropriate, data was transformed to more closely fit a
Gaussian distribution. Statistical analyses used were Student's
t-test, analysis of variance, analysis of covariance, and Fisher's
exact test. Within-group changes were studied both by repeated
measures of analysis of variance and by transformation to percent
change over time.
RESULTS
All 87 women who participated in the study were white with a mean
age of 52.8 years, mean weight of 135.1 pounds, and mean height of
64.6 inches (Table III).
TABLE III
__________________________________________________________________________
Summary of Patient Characteristics Group A Group B Group C Group D
Group E Group F Group G Overall (n = 10) (n = 12) (n = 12) (n = 14)
(n = 13) (n = 14) (n = 12) (n = 87)
__________________________________________________________________________
Age Mean 53.8 53.1 52.0 52.0 53.6 52.4 52.8 52.8 Range 50-57 48-58
47-57 37-58 47-58 48-59 42-58 37-59 Weight (lb) Mean 132.6 130.7
136.3 140.9 136.0 131.9 136.7 135.1 Range 121-150 106-154 112-164
103-165 103-171 96-169 112-163 96-171 Height (in) Mean 63.8 64.7
64.7 65.4 65.0 63.7 65.0 64.6 Range 61-65 60-68 59-69 61-68 62-68
55-69 60-68 55-69 Postmenopausal duration (mo) Mean 31.1 28.1 27.9
28.4 37.8 33.9 36.2 32.0 Range 16-51 12-59 15-53 13-45 15-59 16-54
12-59 12-59 Hot flushes (No./day) Mean 3.0 7.1 8.9 5.6 8.4 7.3 5.6
6.6 Range 0-5 1-15 0-20 1-20 0-12 1-25 1-16 0-25 Duration (mo) Mean
41.3 31.8 21.8 36.6 36.3 48.1 48.8 38.0 Range 2-105 12-92 7-45
2-188 6-59 7-117 1-116 1-188 Drop outs (n) 0 4 1 1 2 4 1 13
__________________________________________________________________________
The average postmenopausal duration was 32 months, with an average
of 6.8 hot flushes per day experienced over an average of 38
months. There were no statistically significant differences among
groups in duration since menopause before study entry, number of
hot flushes, duration of hot flushes, diet, or level of
exercise.
Thirteen women dropped out over the 12-month observation period
(Table III). The screening mammogram for one participant receiving
the combination 10/0.5 (Group E) was read as suspicious. Before
study entry, a surgical consultation was obtained. A 3-month
follow-up mammogram was recommended and subsequently led to needle
biopsy that revealed carcinoma in situ. A diagnosis of superficial
thrombophlebitis led to the withdrawal at 1 month of a woman
receiving the combination 20/1 (Group C). A venogram for this
participant was negative for deep venous thrombosis. Three women
receiving sequential treatment (Group B, at 3, 6, and 7 months of
treatment) and one woman receiving combination 5/1 (Group F, at 1
month of therapy) withdrew from the study because of vaginal
bleeding. Other reasons cited for withdrawal were constipation (two
combination 5/1 (Group F) users after 1 and 2 months), nausea (one
sequential, Group B user after 1 month), depression (one
combination 10/1, Group D user after 2 months), viral pneumonia
(one combination 5/0.5, Group G user after 3 months),
cholelithiasis (one combination 10/0.5, Group E user after 11
months), and being tired of participation (one combination 5/1,
Group F user after 3 months). After withdrawals were excluded, the
various groups remained similar in demographics (age, weight,
height), in duration since menopause, and in their experience of
hot flushes. For the findings reported, Table III, dropouts were
excluded from analyses.
The average number of hot flushes per week declined over time.
Although the calcium-only group demonstrated a decline, this was
not statistically significant, in contrast to the decline noted
with all hormonal treatment groups. The groups differed, however,
in their rate of decline of hot flushes. Women using a continuous
estrogen-progestin regimen (Groups C through G) had an earlier
reduction in their frequency of hot flushes when compared with
women using the conventional sequential estrogen-progestin program
(Group B). Compared with women who received only calcium (Group A),
women receiving sequential estrogen-progestin (Group B) did not
achieve a statistically significant (p<0.05) suppression of hot
flushes until 8 months of treatment, while the women on a regimen
of continuous therapy showed a significant reduction (p<0.05) by
the second month of treatment. The variation around the mean was
minimal and similar in all groups. Reduction in frequency of hot
flushes was accompanied by improvements in vaginal dryness,
dyspareunia, depression, insomnia, and fatigue. The number of women
initially reporting these symptoms, however, was insufficient to
perform statistical analyses for comparison among groups.
All treatment groups reported vaginal bleeding (defined as enough
bleeding to necessitate use of tampons or pads) and spotting
(bleeding not necessitating sanitary protection) in the early
months of therapy. As mentioned above, three sequential users
(Group B) withdrew because of vaginal bleeding, and after 12 months
all eight remaining sequential users were still reporting vaginal
bleeding and spotting. Only one continuous user withdrew because of
vaginal bleeding; after 12 months none of the continuous users was
bleeding and only four of 56 were reported spotting. After 12
months the difference in bleeding and spotting between sequential
and continuous users was significant by Fisher's exact test
(p<10.sup.6). Furthermore, the spotting reported by continuous
users varied across the groups and thus was not related to
dose.
The endometrial biopsy specimens revealed no cases of hyperplasia
or neoplasia. At 12 months four sequential users had secretory
endometrium and one sequential user had mixed
secretory-proliferative activity. The remaining three sequential
users had inactive endometrium or insufficient tissue for
diagnosis. One continuous user had secretory endometrium
(combination 20/1) while 43 continuous users had inactive
endometrium or insufficient tissue for diagnosis. Three women in
the continuous therapy groups (one each in Groups C, D, and E) were
found to have endometrial polyps in the 12-month biopsy specimens,
although none was found in the screening biopsy specimens.
Histologically, both stromal and glandular elements of the polyps
were benign in appearance. Only one of the three women with
endometrial polyps (Group C) reported vaginal spotting. A total of
18 subjects did not undergo screening biopsy because we were unable
to pass a uterine sound. For the same reason 12 of these women
could not undergo biopsy at the end of the observation period.
These subjects were evenly distributed among the treatment
groups.
At baseline, there were no differences among the groups in bone
density (p=0.61). After 12 months, the bone densities of the women
taking calcium only (Group A) remained unchanged (p=0.47). Use of
estrogen-progestin, regardless of the regimen, in contrast to
calcium only, was associated with an increase in bone density
(p=0.005). All doses of continuous combination therapy, even the
lowest combination dose of 5/0.5 (Group g), produced a significant
gain in bone density (p=0.001). The gain in bone density
corresponded directly with the dose of estrogen; however, analysis
of the dose-response relationship was limited by the small sample
sizes. The increase in bone density and tendency for a
dose-response relationship was replicated in analysis of
covariance, adjusting for baseline bone density and for duration
since menopause.
There were no differences among groups in baseline values for serum
phosphorus, serum alkaline phosphatase, bone Gla protein, urinary
calcium/creatinine ratio, or hydroxyproline/creatinine ratio. For
serum calcium Group A (calcium only) had a lower baseline level
than the baseline values for estrogen-progestin users (p=0.033).
After 12 months the serum calcium level increased significantly in
Group A (p=0.043) but did not change over time for the sequential
(p=0.69) and continuous (p=0.40) estrogen-progestin users. At 12
months there were no group differences (p=0.26). Serum phosphorus
values decreased from baseline in women receiving continuous
therapy (p=0.0001) but not in those women receiving sequential
(p=0.91) or calcium-only (p=0.33) treatment. The continuous users
differed from both sequential users (p=0.042) and calcium-only
users (p=0.001) in magnitude of change from the baseline. Bone Gla
protein and serum alkaline phosphatase did not change from baseline
values for the calcium only users (p=0.98 and p=0.28,
respectively), but both decreased significantly in all
estrogen-progestin groups (p=0.0001). The decline in Gla protein
(about 66% from baseline) and in alkaline phosphatase (about 9.6%
from baseline) was the same for sequential therapy as for
continuous estrogen-progestin treatment (p=0.76 and p=0.96,
respectively). All groups experienced a decline in urinary
hydroxyproline/creatinine ratio (p<0.05), and there were no
differences between calcium-only (Group a) users and hormone users
(Groups B through G). The urinary calcium/creatinine ratio analysis
yielded inconsistent results. At baseline, the continuous therapy
and calcium-only groups did not differ in either total cholesterol
(p=0.41) or LDL-cholesterol (p=0.83). Compared with the
calcium-only group and continuous estrogen-progestin users, the
sequential estrogen-progestin users, the sequential
estrogen-progestin users had both significantly lower total
cholesterol (p=0.014) and significantly lower LDL-cholesterol
(p=0.025). There were no group differences, at baseline, for
HDL-cholesterol (p=0.88) or triglycerides (p=0.14). After 12 months
the calcium-only group showed an increase in total cholesterol
(p=0.003) and LDL-cholesterol (p=0.011 ) but no change in
HDL-cholesterol (p=0.45) or triglycerides (p=0.46) (Table IV).
TABLE IV ______________________________________ Mean Lipid Values
After 12 Months of Treatment Calcium Continuous Only Sequential
(Groups (Group A) (Group B) C-G)
______________________________________ Total cholesterol 214.2
198.4 227.6 Baseline value (mg/dl) % Change 12.3 12.7 -3.0 p Value
0.003 0.061 0.072 HDL-cholesterol 66.2 65.3 66.3 Baseline value
(mg/dl) % Change 0.5 -0.2 -0.8 p Value 0.45 0.89 0.13
LDL-cholesterol 132.7 112.8 135.4 Baseline value (mg/dl) % Change
3.1 3.2 -0.4 p Value 0.011 0.093 0.51 Triglyceride 76.7 80.1 110.4
Baseline value (mg/dl) % Change 2.2 8.3 2.0 p Value 0.46 0.000 0.12
1 ______________________________________
The sequential estrogen progestin users tended toward an increase
in total cholesterol (p=0.061), LDL-cholesterol (p=0.093), and
triglycerides (p=0.001), but HDL cholesterol remained the same
(p=0.89). In contrast, the continuous users tended toward a
decrease in total cholesterol (p=0.072), while HDL-cholesterol
(p=0.13), LDL-cholesterol (p=0.51), and triglycerides (p=0.12)
remained without significant change. The changes in total
cholesterol and LDL-cholesterol experienced by the continuous users
differed from those experienced by the sequential
estrogen-progestin users (p=0.019 and p=0.029, respectively); group
differences in HDL-cholesterol (p=0.19) and triglycerides (p=0.09)
were not significant.
There were no significant changes or group differences observed in
blood pressure or body weight. In addition, there were no
clinically significant effects on the hematopoietic system,
electrolytes, renal function, fasting blood glucose, mammography,
or Papanicolaou smear.
In summary, it was found that continuous ethinyl estradiol and
norethindrone acetate are effective for improving postmenopausal
bone metabolism and reducing symptoms of the postmenopausal period
with significantly less annoying vaginal bleeding. These effects
were found even at the lowest doses studied and occurred without
adverse effects on lipid metabolism.
The lowest dose tablet used in the study was effective in
increasing bone density. The minimal dose of ethinyl estradiol
required to improve bone metabolism previously had been established
at 20 mcg. It was found that combination with norethindrone acetate
lowers the threshold to at least 5 mcg.
Lipid metabolism in the women after 12 months of sequential
estrogen-progestin therapy was similar to the lipid changes in
women receiving calcium only; levels of both total cholesterol and
LDL-cholesterol increased. In contrast, after 12 months of
continuous estrogen-progestin therapy women had lower total
cholesterol with LDL-cholesterol remaining at baseline. The women
who participated in the study had higher HDL-cholesterol levels
(mean 66.7 mg/dl) and lower total cholesterol levels (mean 221.9
mg/dl) than the mean levels at the 50th percentile reported for
white women at ages 55 to 64 (60 and 244 mg/dl, respectively). A
common statistical phenomenon, called regression toward the mean,
may partially explain the results. Women who had lipid values most
extreme from the "norm" at baseline were likely to have repeat
values move in the direction of the norm. It has also been noted
that measures of lipid metabolism lack sufficient sensitivity to
detect small changes over time.
The full report of the above described clinical study is in Am J
Obstet Gynecol 1990; 162:438-46.
The present invention includes combinations of synthetic estrogens
and synthetic progestogens and is not limited to the combination
and continuous administration of ethinyl estradiol and
norethindrone acetate. For example, continuous administration of a
combination of conjugated equine estrogen and medroxyprogesterone
acetate is described in Obstet Gynecol 1988;71:39. Continuous
administration of 17.beta.-estradiol and norethindrone acetate is
described in Brit J Obstet and Gynecol 1990;97:1087-1092. Thus,
combinations of estrogens and progestogens at the fixed ratio and
dosage of the present invention and administration of such in a
continuous sequence provides relief of menopausal symptoms. The
fixed compositions of the present invention can be prepared by an
improved process adaptable as well for ultra low dose formulations
which comprise dissolving together in one vessel both the
estrogenic and progestogenic ingredients, e.g., norethindrone
acetate and ethinyl estradiol in alcohol; plating the solution of
ingredients onto a mixture of lactose and excipients, removing the
alcohol by drying, adding incrementally other excipients, and
blending in a lubricant, e.g., calcium stearate, and compressing
the resulting mixture into tablets.
The process may be illustrated by the following scheme:
______________________________________ BLENDING SCHEME FOR TWO
COMPONENT DRUG DILUTION USED IN NORETHINDRONE ACETATE/ETHINYL
ESTRADIOL TABLET GRANULATION BLENDED IN P-K LIQUID/SOLIDS BLENDER
WITH INTENSIFIER BAR A. ETHINYL ESTRADIOL NORETHINDRONE ACETATE
ALCOHOL SD 3A* DISSOLVE ETHINYL ESTRADIOL AND NORETHIN- DRONE
ACETATE IN SD 3A ALCOHOL WITH GENTLE STIRRING. B. LACTOSE FAST FLO
TWO COMPONENT DRUG SOLUTION ADD "A" TO "B" IN P-K BLENDER WITH
INTENSIFIER BAR AND BLENDER ON. RINSE WITH ADDITIONAL ALCOHOL (20
ml/1 kg.). BLEND WITH INTENSIFIER BAR FOR 5 MINUTES. REMOVE AND DRY
UNTIL ALL ALCOHOL IS EVAPORATED. SCREEN THROUGH A #30 SCREEN C.
DRUG GRANULATION MICROCRYSTALLINE CELLULOSE STARCH CORN NF ADD
MICROCRYSTALLINE CELLULOSE WITH STARCH AND BLEND FOR MINUTES WITH
INTENSIFIER BAR. D. DRUG GRANULATION MICROCRYSTALLINE CELLULOSE
STARCH CORN NF CALCIUM STEARATE ADD CALCIUM STEARATE AND BLEND FOR
1 MINUTE WITH INTENSIFIER BAR AND 1 MINUTE WITHOUT INTENSIFIER BAR.
______________________________________ *Alcohol SD 3A = Denatured
anhydrous ethanol 100 parts with 5 parts methanol. Drying may also
be carried out under vacuum in this equipment.
The invention is illustrated by the following example(s).
EXAMPLE 1
1.00 g ethinyl estradiol U.S.P., (0.5% dilution, 5% excess) was
combined with 0.5 g norethindrone acetate U.S.P. 8.66 g Hydrous
Fast Flo lactose U.S.P. and 7.00 g corn starch N.F. in a suitable
liquids/solids PK blender equipped with intensifier bar. The
ingredients were blended for five minutes. All mixing was done
using the intensifier bar unless specified otherwise.
17.50 g microcrystalline cellulose NF Powder was added to the
resultant blend and mixed for 5 minutes. 34.64 g Hydrous Fast Flo
lactose U.S.P. was added and all ingredients were blended for five
minutes.
Thereafter, 0.70 g calcium stearate NF powder was added and blended
with the intensifier bar for one minute and without it for one
minute.
The final mixture was compressed 70 mg on 7/32 FFBE punches at 4-6
kg hardness and about 0.085 inch gauge. One thousand tablets were
produced from the composition.
EXAMPLES 2-4
Using the same procedure described above, tablets were produced
using the following ingredients:
______________________________________ Ingredient Ex. 2 Ex. 3 Ex. 4
______________________________________ Ethinyl estradiol, U.S.P.
2.00 1.00 2.00 (0.5% dilution, w/5% excess) Norethindrone acetate,
U.S.P. 0.50 1.00 1.00 Lactose, Hydrous Fast Flo, U.S.P. Initial
Quantity: 8.46 8.56 8.36 Added Quantity 33.84 34.24 33.44 Corn
Starch, NF 7.00 7.00 7.00 Microcrystalline cellulose 17.50 17.50
17.50 Calcium stearate 0.70 0.70 0.70
______________________________________
EXAMPLE 5
______________________________________ Each Per Tablet Ingredients
1000 Tablets ______________________________________ 1.0 mcg 1.
Ethinyl Estradiol U.S.P. 0.001 g 100.0 mcg 2. Norethindrone Acetate
0.100 g U.S.P. 3. Alcohol SD 3A 10.000 ml Anhydrous q.s. 4. Lactose
USP Hydrous 68.833 g (Fast Flo) q.s. 5. Starch Corn NF 10.000 g
q.s. 6. Cellulose Microcry- 20.000 g stalline NF Granular (PH-102)
q.s. 7. F.D. & C. Blue #1 Lake 0.066 g HT 31% q.s. 8. Calcium
Stearate NF 1.000 g q.s. 100.000 mg To make 100.000 g
______________________________________
Component 7 was added to components 4 and 5 and blended in a
suitable size P-K liquid/solids blender with intensifier bar for
five minutes. Component 6 was then added and blended with
intensifier bar for another five minutes.
In a separate container, components 1 and 2, the active
ingredients, were dissolved in alcohol, component 3, and then added
to the blender at a sufficient rate through intensifier bar with
bar and blender on. The blender was rinsed with additional alcohol,
3, (20 ml/l kg) through intensifier bar with blender and bar on.
The entire mixture was blended an additional five minutes.
The damp granulated material was removed from the blender and air
dried until all the alcohol evaporated, or preferably vacuum dried.
The material was then reblended with intensifier bar for five
minutes. Component 8 was added and blended with intensifier bar for
one minute and without for one minute.
The final mixture was compressed 100 mg on 0.208".times.0.250 Oval
punches at 6-9 kg units hardness and about 0.130" thickness. One
thousand tablets were produced from the composition.
* * * * *